Although degeneration of cortical cholinergic innervation is a consistent feature of Alzheimer's disease (AD), many questions concerning the nature and origin of this degeneration remain unanswered. Of note, no comprehensive histochemical survey exists of the cholinergic system in AD. The major goal of the research outlined in this proposal is to provide a comprehensive survey of the cholinergic system in AD using histochemical and morphological methods. The existence of regional variations in the loss of cortical cholinergic fibers in AD will be determined using a histochemical method for acetylcholinesterase (AChE). the loss in number and size of the cholinergic neurons of the basal forebrain and brainstem in AD brains will be determined in all sectors of these nuclei using immunohistochemistry for choline acetyltransferase. Then, the relationship between the loss of these cholinergic markers and the density of cortical and subcortical plaques and tangles, the density of AChE-and butyrylcholinesterase (BChE)-positive cortical plaques and tangles and the loss of AChE-positive cortical pyramidal neurons will be determined. In addition, the extent of AD-related loss in the number and size of the dopaminergic neurons of the ventral tegmental area, the noradrenergic neurons of the locus coeruleus and the serotoninergic neurons of raphe will be determined and compared to the loss observed in cholinergic neurons of the basal forebrain and brainstem. The relationship between the loss observed in each nucleus and the density of cortical plaques and tangles as well as plaques and tangles in each nucleus will also be determined. All of these measures will be determined in each AD brain and compared to a control brain matched with it. The results will provide detailed information on the status of cholinergic neurons and axons in AD, will add to our knowledge concerning the site at which this cholinergic pathology is initiated and therefore will have important implications for the strategies chosen for drug therapy in AD. Further studies will determine experimentally, the effect of loss of cortical neurons on the cholinergic system. Adult rats will receive ibotenic acid lesions of the frontoparietal cortex and hippocampus, and the effect of these lesions on the density of cortical cholinergic fibers as well as the various neurochemicals contained within the cholinergic neurons of the basal forebrain (ChAT, nerve growth factor receptors, galanin and NADPH-diapharase) determined.